Benzodiazepines chronic administration

These observations question the role of noradrenaline as an initiator of anxiety as does the finding that the anti-anxiety drug, buspirone (see Chapter 9), increases the concentration of noradrenaline in the extracellular fluid in the frontal cortex of freely-moving rats (Done and Sharp 1994). Whether this is because buspirone is metabolised to l-(2-pyrimidinyl)-piperazine (1-PP), which is an a2-adrenoceptor antagonist, is uncertain. Unfortunately, no studies have investigated the effects of chronic administration of this drug on noradrenergic transmission this could be important because, unlike benzodiazepines, buspirone is effective therapeutically only after several weeks of treatment. 

The relative contribution of the active metabolites of the benzodiazepines to the overall therapeutic effect of the parent compound will depend on the concentration of the metabolite formed, its agonist potency at central benzodiazepine receptors and its lipophilicity. For example, after the chronic administration of diazepam, desmethyldiazepam accumulates in the brain. As this metabolite has potency at the benzodiazepine receptors equal to diazepam, the metabolite probably plays an important part in the overall action of diazepam. In the case of clobazam, however, even though the active metabolite desmethylclobazam is present in higher concentrations than the parent compound after chronic administration, it has a lower potency than clobazam and therefore is of less importance than the parent compound with regard to the anxiolytic effect. 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

In contrast to these reports of benzodiazepine-induced motor impairment, Kumar et al.138 found that chronic administration of 1 mg lorazepam and 0.5 mg alprazolam for 5 days had no effect on fine motor coordination as assessed using a standard pegboard test. Additionally, Tobler et al.139 reported that performance on a typing test was not impaired the day after an acute dose of 7.5 mg midazolam. 

Actions at benzodiazepine receptors are thought to underlie virtually all the pharmacological actions of the benzodiazepines, those that are desirable as well as those that are undesirable. This includes the desirable therapeutic actions of benzodiazepines as anxiolytics and sedative-hypnotics, as well as anticonvulsants and muscle relaxants. It also includes their undesirable side effects as amnestic agents and as agents that cause adaptations at the benzodiazepine receptor with chronic administration, which are thought to underlie the production of dependence and withdrawal from these agents (see Chapter 13). 

Changes in benzodiazepine receptor function following chronic administration of benzodiazepines... 

In human studies, there is some evidence that withdrawal signs such as nervousness, anxiety and vertigo occur following sub-chronic administration of zopiclone but the frequency and intensity of the withdrawal effects are greater after conventional 1,4-benzodiazepines. No rebound effects have been seen in patients with insomnia who received zolpidem daily for 7-180 days. By contrast, after 3 weeks of abercamil treatment of patients with generalized anxiety disorder possible signs of withdrawal resulted, the incidence of these withdrawal effects being related to doses of abercamil administered. 

After chronic administration of diazepam, i.e. at steady state, plasma concentrations of desmethyidiazepam (the major metabolite in blood) are similar to those of diazepam. The hydroxylated metabolites of the benzodiazepines, together with benzodiazepines which have an hydroxyl group at the C3 position (e.g. lorazepam), are conjugated with glucuronic acid and it is these derivatives which account for the major fraction of the dose excreted in the urine. 

Chronic administration of benzodiazepines—study of differences between benzodiazepines and the potency to induce physiccil dependence in rats. 

Toxic effects may occur with chronic administration, and patients taking diazepam need medical monitoring. In addition, dependence may develop with regular use of benzodiazepines, and withdrawal symptoms may occur with cessation. 

Classical antipsychotic agents induce EPS on chronic administration and also do not treat up to 30% of psychotic patients. Clozapine, a tricyclic benzodiazepine derivative, was the first antipsychotic drug to display a dramatically different pharmacological profile and did so both in animals and clinically. This profile created the concept of a new class of "atypical" antipsychotic drugs. 

Miller LG, Greenblatt DJ, Barnhill JG, et al Chronic benzodiazepine administration, I tolerance is associated with benzodiazepine receptor downregulation and decreased gamma-aminobutyric acidA receptor function. J Pharmacol Exp Ther 246 170-176, 1988a... 

Lenox RH, Manji HK Lithium, in The American Psychiatric Press Textbook of Psychopharmacology. Edited by Nemeroff C, Schatzberg A. Washington, DC, American Psychiatric Press, 1995, pp 303-349 Lenox RH, Watson DG Lithium and the brain a psychopharmacological strategy to a molecular basis for manic-depressive illness. Chn Chem 40(2 309-314, 1994 Lenox RH, Watson DG, Patel J, et al Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res 570 333-340, 1992 Lenzi A, Lazzerini F, Grossi E, et al Use of carbamazepine in acute psychosis a controlled study. J Int Med Res 14 78-84, 1986 Leonard BE Commentary on the mode of action of benzodiazepines. J Psychiatr Res 27 (suppl 1) 193, 1993... 

U.S. Food and Drug Administration for the treatment of insomnia, almost all benzodiazepines may be used for this purpose. Benzodiazepines are most clearly valuable as hypnotics in the hospital setting, where high levels of sensory stimulation, pain, and acute stress may interfere with sleep. The safe, effective, and time-limited use of benzodiazepine hypnotics may, in fact, prevent chronic sleep difficulties (NIMH/NIH Consensus Development Conference Statement 1985). Benzodiazepines are also used to treat akathisia and catatonia and as adjuncts in the treatment of acute mania. 

Miller LG, Greenblatt DJ, Roy RB, et al. Chronic benzodiazepine administration II. Discontinuation syndrome is associated with upregulation of aminobutyric acid receptor complex binding and function. J Pharmacol Exp Ther 1987 246 177-182. 

Consistent with their depressant and sedative effects, benzodiazepines administered acutely typically decrease CFF threshold.119 120 Specifically, significant decreases have been reported for 1 mg alprazolam, 10 mg diazepam, and 15 mg quazepam 121 4 to 11 mg midazolam 122 7.5 to 50 mg oxazepam 123 1 and 2 mg lorazepam 124 and 0.5 mg triazolam and 1 mg flunitrazepam.120 As is evident, this effect on CFF threshold was observed at therapeutic doses of each drug, and when multiple doses were tested, the effect was dose-related. However, there are reports of acute, therapeutic doses of diazepam (5 mg)125 and lorazepam (1 and 2 mg)125,126 having no effect on CFF threshold. One study investigating numerous benzodiazepines120 reported next-day impairment after acute doses of triazolam (0.5 mg) and lormetazepam (1 to 2 mg). No studies were found that examined the effect of chronic benzodiazepine administration on CFF threshold. 

When benzodiazepines are used or abused chronically, they may cause adaptive changes in benzodiazepine receptors such that their power to modulate GABA-A receptors in response to a benzodiazepine decreases with time (Fig. 13—32). These patients may become irritable or anxious or even experience panic attacks if they suddenly stop taking the drugs (Fig. 13—33). This shift in benzodiazepine abusers to a desensitized receptor (Fig. 13—32) may manifest itself as the need to take higher doses of benzodiazepines to get high. This receptor desensitization is most likely to be uncovered once chronic abusive benzodiazepine administration is discontinued, particularly if discontinuation is sudden (Fig. 13-33). This desensitized receptor worsens the impact of benzodiazepine discontinuation because the brain, which is... 

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